Aim: Assigning a disease-locus within the shortest regions of overlap (SRO) shared by deleted/duplicated subjects presenting this disease is a robust mapping approach, although the presence of different malformation traits and their attendance only in a part of the affected subjects can hinder the interpretation. To overcome the problem of incomplete penetrance, we developed an algorithm that we applied to the deletion region 1q23.3-q25, which contains three SROs, each contributing to the abnormal phenotype without clearly distinguishing between the different malformations. We describe six new subjects, including a healthy father and his daughter, with 1q23.3-q25 deletion of different sizes. The aim of this study was to correlate specific abnormal traits to the haploinsufficiency of specific gene/putative regulatory elements.

Methods: Merging cases with those in the literature, we considered four traits, namely intellectual disability (ID), microcephaly, short-hands/feet, and brachydactyly, and conceived a mathematical model to predict with what probability the haploinsufficiency of a specific portion of the deletion region is associated with one of the four malformations.

Results: The haploinsufficiency of PBX1 is strongly associated with ID. DNM3 and LHX4 are confirmed as responsible for growth retardation, whereas ATPIB1 was identified as a new candidate gene for microcephaly, short-hands/feet, and brachydactyly.

Conclusion: Although our model is hampered by long-term position effects of regulatory elements, synergistic cooperation of several genes, and incomplete clinical assessment, it can be useful for contiguous gene syndromes showing a complex pattern of clinical characteristics. Obviously, functional approaches are needed to warrant its reliability.

Stroke is an abrupt loss of brain function, which is caused by the interruption of blood flow to the brain. Several blood biomarkers have been evaluated for the assessment of stroke severity and outcome. However, their roles remain limited in clinical practice. Circulating cell-free deoxyribonucleic acid (DNA) has emerged as a potential biomarker of stroke, as reported from several animal and human studies. In this study, we aim to review the prognostic values of cell-free DNA in stroke from all relevant cohort studies. The PubMed database was searched using keywords, "cell-free DNA" and "stroke" for relevant articles. Twelve studies (n = 946 patients) are included in the final analysis. While the prognostic values of cell-free DNA in predicting functional outcomes and hospital mortality after different types of stroke were highlighted in many studies, the inconsistency in methods hinders comparability between studies. Overall, the knowledge about the potential prognostic ability of cell-free DNA in stroke remains limited and conflicting. More robust studies with consistent methods are needed.

Aim: Kleefstra syndrome (KS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the euchromatic histone lysine methyltransferase 1 gene, EHMT1, due to either a submicroscopic 9q34.3 deletion or a pathogenic EHMT1 variant. KS is characterized by intellectual disability, autistic-like features, heart defects, hypotonia and distinctive facial features. Here, we aimed to (1) identify a unique DNA methylation signature in patients with KS, and (2) demonstrate the efficacy of DNA methylation in predicting the pathogenicity of copy number and sequence variants.

Methods: We assayed genome-wide DNA methylation at > 850,000 CpG sites in the blood of KS patients (n = 10) carrying pathogenic variants in EHMT1 or 9q34.3 deletions, as compared to neurotypical controls (n = 42). Differentially methylated sites were validated using additional KS patients (n = 10) and controls (n = 29) to assess specificity and sensitivity of these patterns.

Results: The DNA methylation signature of KS demonstrated high sensitivity and specificity; controls and KS patients with a confirmed molecular diagnosis were classified correctly. In additional individuals with EHMT1 alterations, including frameshift or missense variants and partial gene duplications, DNA methylation classifications were consistent with clinical presentation. Furthermore, genes containing differentially methylated CpG sites were enriched for functions related to KS features, including heart formation and synaptic activity.

Conclusion: The KS DNA methylation signature did not differ in patients with deletions and variants, supporting haploinsufficiency of EHMT1 as the likely causative mechanism. Beyond this finding, it provides new insights into epigenetic dysregulation associated with KS and can be used to classify individuals with uncertain genomic findings or ambiguous clinical presentations.

Mitochondrial diseases are multi-systemic, heterogeneous groups of diseases that are associated with various neuromuscular problems, cardiovascular disorders, metabolic syndrome, cancer, and obesity. Mitochondrial diseases are due to mutations in mitochondrial DNA or nuclear DNA that can affect the assembly of the mitochondrial components and mitochondrial function. Typically, mitochondrial diseases can be inherited through an autosomal dominant, autosomal recessive or X-linked pattern of inheritance. To date, there are more than 100 mitochondrial diseases identified. However, clinical phenotype heterogeneity is a huge problem for the diagnosis of mitochondrial diseases, as patients with the same mutations exhibit different clinical symptoms. Also, the heteroplasmy/homoplasmy conditions complicate the diagnosis process. Here, in this review, we discuss these challenges and problems in mitochondrial disease diagnosis, focusing on the mutational profile of both primary and secondary mitochondrial diseases. We also review the utilization of next-generation technology and multi-omics strategy to improve the diagnosis. The discussion addresses the current evidence of those applications and the challenges that need some improvement for better diagnosis yield.

Mitochondrial diseases collectively represent the most common cause of inherited metabolic disease. They are estimated to affect at least 1 in 8,000 adults and at least 1 in 250 adults carry a disease-causing genetic mutation. They comprise a heterogeneous group of disorders caused by mutations in either the nuclear or mitochondrial genome, which ultimately result in dysfunction of the critical cellular energy producing mitochondrial respiratory chain. Owing to the key role of mitochondria in energy production, mitochondrial disorders predominantly manifest in tissues with high metabolic demand. However, they demonstrate significant phenotypic and genotypic variability, often rendering the diagnostic process protracted and challenging. Since Luft’s first description of mitochondrial disease nearly 60 years ago, substantial evolution in diagnostic techniques have simultaneously improved the diagnosis and understanding of mitochondrial disease and biology, but the standard diagnostic approach has failed to evolve at the same pace. Although sequencing technologies and analysis for the diagnosis of mitochondrial disease continue to evolve, advances to date, our expanding understanding of mitochondrial diseases and the increasing affordability of these new technologies justify a paradigm shift in the diagnostic approach. We review the progression, impact and challenges of diagnosing mitochondrial diseases and propose a minimally invasive “genetics first” approach incorporating stratification using non-invasive biomarkers, followed by non-targeted next-generation sequencing, such as whole genome sequencing. Such an approach may improve diagnostic yield and streamline diagnosis, leaving invasive investigations to address diagnostic challenges and functional validation of novel variants.

Suicide is a dangerous clinical event causing 2% of human mortality. Due to its inherent danger to life and complexity, suicide studies are in high demand. Many resources have been allocated to the development of predicting suicides, its prevention and useful medical interventions so that biomedical and scientific study of the subject is indispensable. Historically, knowledge on suicide was largely based on mental illness studies. The diagnosis of suicide,mood disorders and the treatments have been reported since over 2000 years ago (Hippocrates in 460-377, BC). Despite a long history of association between suicide and mood disorder, the related terminology have evolved greatly. Yet, mortality reduction has been minimal despite many diagnostic and therapeutic studies and no effective therapeutic means have been developed. To improve on this scenario, we review the history and literature on suicide.

Aim: Genetic variants on metabolic and transport enzymes are good candidates to explain inter-individual differences in response to antipsychotics. The aim of this study is to evaluate and compare the influence of the CYP2D6, CYPC19, CYP1A2 and ABCB1 variants on plasma levels, treatment response and side effects of antipsychotics.

Methods: Twenty polymorphisms in selected genes were genotyped in 318 patients diagnosed with schizophrenia, schizoaffective or delusional disorder treated with antipsychotics (clozapine, olanzapine, paliperidone, risperidone, aripiprazole and quetiapine). Plasma drug levels were determined after 6 weeks of treatment. The Positive and Negative Symptoms Scale (PANSS) and UKU scale of side effects were recorded at baseline and after 12 weeks of treatment. The effect of gene variants on plasma drug levels, treatment response and adverse effects were examined by multinomial regression.

Results:CYP1A2 was found to be associated with psychic side effects (P = 0.02), with variants predicting higher enzyme activity associated with lower adverse effects, and was the strongest predictor for this adverse effect of all the studied factors. Functional variants in CYP genes were associated with plasma level differences, with higher activity variants associated with lower plasma levels. No association with improvement of the condition, as measured by the PANSS score, was found in this study.

Conclusion: The results suggest that increased CYP1A2 activity protects against psychic side effects. Few studies have evaluated the impact of genetic factors on treatment response or side effects, and only in relation to a selection of adverse reactions. These results are a step towards better understanding of the factors behind the different aspects of clinical outcomes, such as various adverse effects.

Mitochondrial disorders (MD) include a large group of maternally inherited, autosomal dominant, or recessive genetic syndromes caused by mitochondrial dysfunction. MD can be diagnosed at any age and many of them show a multisystem presentation with variable combinations of symptoms. Given the important role of mitochondria in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany MD. Movement disorders (MoD), either hypo- or hyperkinetic type, are reported in MD, but the real incidence and a detailed characterization of these features are not addressed in population-based studies. Dystonia, usually in the context of Leigh syndrome, is the main extrapyramidal movement disorder in pediatric MD patients; whereas parkinsonism is the most prevalent hypokinetic disorder in adult MD patients. Ataxia is a common feature in MD, in both the pediatric and adult MD populations. Other MoD, such as myoclonus, chorea, or tremor, may also occur in MD. MoD manifest more frequently in the context of a complex phenotype but rarely can be isolated. From a genetic point of view, MoD are described in patients with either mutations in mtDNA or in nuclear genes related to mitochondria, and the same gene can be associated with different types of MoD. Recent studies demonstrate that the dopaminergic nigrostriatal system is very vulnerable to mitochondrial dysfunction and defects of mtDNA maintenance are frequently associated with a nigrostriatal degeneration, which may explain the pathophysiological mechanism. Therapeutic interventions for MoD in MD do not differ from treatment options used for MoD with different etiopathological background. Some forms benefit from specific treatments, e.g., primary Coenzyme Q10 deficiencies. Newer therapeutic strategies have been pursued which act on different mechanisms of mitochondrial dysfunction, but clinical trials are warranted to improve the management of MD patients.

The broad application of next-generation sequencing in genetic diagnostics opens up vast possibilities for personalized treatment of patients with genetic disorders including monogenic epilepsies. To translate genetic findings into personalized medicine, mechanistic studies of the individual pathogenic variants and drug screening in patient-specific in vitro models are very crucial. Recently, human induced pluripotent stem cell (hiPSC) technologies have made it possible to generate patient-specific pluripotent cells, which can be directed to differentiate into any given cell type. These hiPSCs are ideal for generating neurons to investigate specific neurological/neurodevelopmental disorders. While two-dimensional single-cell models of hiPSC-derived neurons provide reliable investigation of synaptic transmission and plasticity, cerebral organoids are superior in regard to functional characterization and the study of cell-cell interactions in three-dimensional structures. In this review, we focus on monogenic epilepsies and discuss the application of hiPSC models in personalized drug treatment based on the patient’s specific genetic variants.

Autism spectrum disorder (ASD) is characterized by impairments in social interaction and the presence of stereotypy and restrictive behavior. The clinical heterogeneity of ASD makes it difficult to explain the mechanisms underlying the disease. In recent years, the association between autophagy and neuropsychiatric diseases has been investigated. In this review, we aimed elucidate the relationship between autism and autophagy mechanism in well-known autism relevant animal models. Autophagy is a cell-protective mechanism that allows cell survival in low nutrient conditions, often through the degradation of aging and damaged proteins and organelles. The target of rapamycin (TOR) complex is activated for the activation of autophagy. Apart from mTOR animal models, the valproic acid model is frequently used in autism studies. The coiled-coil and C2 domain containing 1A (CC2D1A) gene is one of the new candidate genes associated with ASD. In a recent study that used Cc2d1a knock-out mice, microtubule-associated protein 1A/1B-light chain 3 (LC3) and Beclin 1 expression levels were dysregulated in the hippocampus. It is thought that the impaired autophagy mechanism contributes to the etiology of ASD. These results showed that CC2D1A acts as a new biological pathway in autophagy. Choosing the right model is crucial for ASD studies, and further progress will be made as these results become available in the clinic. In particular, it is expected that further studies on CC2D1A will provide new information in this field.

As the opioid epidemic continues to grow across the United States, the number of patients requiring treatment for opioid use disorder continues to climb. Although medication-assisted treatment presents a highly effective tool that can help address this epidemic, its use has been limited. Nonetheless, with easier dosing protocols (compared to the more complex dosing required of methadone due to its long and variable half-life) and fewer prescribing limitations (may be prescribed outside the setting of federally approved clinics), the increase in buprenorphine use in the United States has been dramatic in recent years. Despite buprenorphine’s demonstrated efficacy, patient-specific factors can alter the response to the medications, which may lead to treatment failure in some patients. Clinical characteristics (sex, concurrent medications, and mental health comorbidities) as well as social determinants of health (housing status, involvement with the criminal justice system, and socioeconomic status) may impact treatment outcomes. Furthermore, a growing body of data suggests that genetic variations can alter pharmacological effects and influence therapeutic response. This review will cover the available pharmacogenomic data for the use of buprenorphine in the management of opioid use disorders. Pharmacogenomic determinants that affect opioid receptors, the dopaminergic system, metabolism of buprenorphine, and adverse events are discussed. Although much of the existing data comes from observational studies, clinical research is ongoing. Nevertheless, the development of pharmacogenomic-guided strategies has the potential to reduce opioid misuse, improve clinical outcomes, and save healthcare resources.

The identification of the genetic causes and the underlying pathogenic mechanisms in early-onset epilepsies has proved to be essential in improving the efficacy of therapeutic decisions and the overall patient management, especially in the era of precision medicine. We report an infant presenting with a cluster of focal motor seizures with autonomic manifestations at day 3 of life. Electroencephalograms showed multifocal epileptic abnormalities and a burst-suppression pattern. Neurological examination showed poor visual fixation and hypotonia. Neuroimaging was normal. Seizures remitted with phenytoin and were well-controlled after the switch to oral carbamazepine. In the hypothesis of a genetic etiology, next-generation sequencing panel for epileptic encephalopathies was performed and identified a de novo missense mutation in KCNQ2: c.1742G>A; p.(Arg581Gln) (NM_172107.2). This case report highlights the importance of the early recognition of the electroclinical phenotype and the detection of the underlying genetic cause in the implementation of “tailored” therapies in early-onset genetic epilepsies.